Monoamine oxidases (MAO) are enzymes to catalyze amines in oxidative deamination reaction of monoamines. There are two subtypes of MAO: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), both of which exist in neurons and astrocytes, but differ in the specificity to substrates and inhibitors. In addition to the central nervous system, MAO-A exists also in liver, gastrointestinal tract and placenta, whereas MAO-B exists mainly in platelets
Monoamine oxidases may be an important target of drug action, and a number of drugs have been developed successfully from of the nonoamine oxidases inhibitors. Selective MAO-A inhibitors, such as Clorgiline, can be used for treating depression, and selective MAO-B inhibitors, such as Rasagiline and Selegiline, can be used for treating Parkinson's disease.
In the 1970s, it was found that cholinergic neurotransmitter antagonists can significantly damage the memory function of mice (Deutsch. Science, 1971, 174(4011): 788-794), which indicats that the cholinergic nervous system may play an important role for learning and memory capacity of the brain. Since then, a series of experiments proved that the brain cholinergic system has important effect to consciousness, attention and memory. Cholinesterase becomes an important target of drug action, for instance, acetyl cholinesterase inhibitors (AChEI), mainly through reversible inhibition of acetylcholinesterase, may reduce the speed of acetylcholine degradation and enhance acetylcholine level for improving AD patients' abonormity in memory, thinking, language, judgment, and other brain functions. Currently, the acetyl cholinesterase inhibitors approved by the FDA of the United States for treating AD mainly include Tacrine, Donepezil, Rivastigmine, and Galantamine.
Oxidative stress refers to a condition in physiological processes that the body, when stimulated, produces a large number of oxide intermediates to cause imbalance between reactive oxygen species and antioxidant system. Such imbalances tend to cause excessive generation of free radicals and deminition of the activity of antioxidant system and thus induce the body's oxidative damage. These free radicals include reactive oxygen species (ROS) and reactive nitrogen species (RNS). Free radicals are rather complex in generation, and are closely related to various of physiological and biochemical process (Conrad et al. J Neurochem Int. 2013 April; 62 (5):738-49). Lipid peroxidation may easily occurs as a large amount of polyunsaturated fatty acids exist in the phospholipid bilayer of the neurons, and thus, neuronal cells, as compared to other types of cells, are more susceptible to oxidative stress (Facecchia et al. J Toxicol 2011; 2011, 683-728). Damage of oxygen metabolism to central nervous system may produce more severe oxidative stress effect and further damage of the nervous system (Mohsenzadegan et al. Irfan J Allergy Asthma Immunol, 2012 September; 11 (3):203-16). Under normal conditions, excessive free radicals and reactive oxygen species such as hydrogen peroxide (H2O2), singlet oxygen and ozone (O3) in the body can be scavenged quickly by antioxidant system, but under pathological conditions, such scavenging activity diminishes. The accumulation of reactive oxygen species may induce nucleic acid fracture, enzymatic inactivation, depolymerization of polysaccharide, and peroxidation of lipids, and eventually lead to neuronal death (Yan et al. Free Radic Biol Med. 2013 September; 62:90-101). There are many factors which can cause oxidative stress, and, for example, Aβ, metal ions and mitochondria are considered to play important roles in the process of oxidative stress.
The content of soluble Aβ and hydrogen peroxide production rate show good linear relationship. Aβ can effect the permeability of calcium ion channels, activate NADPH oxidase II(NOX2), make electrons transferred from NADPH to oxygen, increase ROS generation rate, and, at the same time, Aβ has strong affinity metal ions with REDOX activity (Pimentel et al., Oxid Med Cell Longev. 2012; 2012:132-146), after it combined with these active metal ions, it may produce hydrogen peroxide. Studies have shown that pro-oxidant can promote the formation of Aβ, whereas antioxidants, such as vitamin E and some other free radical scavengers, can prevent the damage of Aβ to neurons, and improve cognitive impairment.
Mitochondria is a major site for oxidation-reduction reactions and a major donor of energy in the cells, the free radicals it produced are 90% more than the total amount of free radicals inside the cells, and thus, the normal functions of mitochondria is important to maintain the normal physiological activity (Yan et al. Free Radic Biol Med. 2013, 62:90-101). It has been thought that a variety of neurodegenerative diseases, such as AD, PD, HD, ALS and PSP, are caused mainly from neuron mitochondrial dysfunction (Du et al. Int J Biochem Cell Biol. 2010, 42(5): 560-572). Based on quantitative morphology count of different types of mitochondria (normal, partial damaged or completely damaged) in the brain neurons of AD patients, it is found that as compared with the normal brain neurons of the same age, the content of normal mitochondria in the AD brain neurons decreased significantly, and the content of completely damaged mitochondria increased significantly (Beal et al. Curr Opin Neurobiol. 1996 6(5): 661-6666). The damage of mitochondria induces oxidative damage of neurons, which showed in two expects: one is to cause abnormal function of the electron transport chain (ETC) and make the content of free radicals increased; and the other is to decrease the vitality of mitochondria in antioxidant system through lowering the content of antioxidant small molecules, such as Glutathione, coenzyme Q, vitamin C, vitamin E and enzyme catalysis in the mitochondria.
Existing clinical methods for the treatment of PD are rather limited, and also are merely for temporary alleviation of diseases and not able to stop further attenuation of nerve cells. As there are several different reasons for PD to occur, no satisfied effects could be obtained if only a single-route or single-target administration is given, or the “one-drug and one-target” approach could not be used for fundamental treatment of such diseases. Multifunctional drugs are those having multiple treatment mechanisms for the treatment of a single disease, and many physicians and scientists believed that such multifunctional drugs with multiple functions to multiple targets of a single disease should have greater potential over currently well accepted “one-drug and one-target” approach. The diseases that the multifunctional drugs are used for treatment mainly include difficult and complicated diseases such as depression, schizophrenia, cognitive and movement disorders (Morphy et al. Drug Discov Today. 2004, 9(15): 641-651). Many drugs, however, when used in excess dosage, may show multiple mechanisms not related to the disease itself and thus could induce many side effects, and of course such drugs cannot be considered as multifunctional drugs (Stahl et al. CNS Spectr. 2009, 14(2): 71-73).
Combination drug therapies are often utilized to treat some pathologically complicated diseases, in other words, by using of multiple kinds of drugs which are directed to different targets of a single disease. For instance, human immunodeficiency virus (HIV) reverse transcriptase inhibitors and HIV protease inhibitors are used in combination for the treatment of acquired immune deficiency syndrome (AIDS). Another example is bronchodilator developed for the treatment of inflammation and bronchial asthma, and such drug is a compound preparation from three drug components of fluticasone, corticosteroids and salmeterol, and has been approved by the FDA in the United States. However, combination drug therapy of multiple drug molecules may cause many problems. One of the most important problem is that drug molecules may differ in the properties of such as bioavailability and pharmacokinetic. Even worse, the combination may bring about more toxic or side effects, and different drug molecules may also have interactions. In elderly patients and high risk groups, these side effects may be life threatening. Therefore, the drug research and development on multifunctional drug molecules of “one-drug and multi-targets” approach, which has advantageous of low toxicity, high efficacy, flexible dosage regimen have attracted more and more attention in drug research (Van et al. J Neurochem. 2006, 99(4): 1033-1048).
It is reported that drugs with dual mechanism was developed for treating Alzheimer's disease. Researchers believed that, combination molecules containing both cholinesterase inhibitors and SERT inhibitors can be used to treat AD and at the same time treat the accompanying depression. The use of multi-functional drug compounds with both cholinesterase and SERT inhibiting activities can avoid the side effects caused by excessive undesirable cholinergic stimulation (Toda et al. Bioorg Med Chem. 2003, 11(20): 4389-4415).